Certain 1-(trifluoromethylphenyl sulfonamidoalkyl) azacycloalkanes and their use as anti-arrhythmic agents

ABSTRACT

Pharmaceutical compositions which comprise a compound of the formula (I): ##STR1## or a salt thereof wherein NR 2  represents a piperidyl, pyrrolidyl, morpholino or N-methyl-piperazyl group any of which may substituted by one or two methyl groups; R 1  represents fluorine, chlorine, bromine, iodine, lower alkoxyl, hydroxyl, acetoxyl, nitro, cyano, amino, dimethylamino, lower alkyl, trifluoromethyl, methylthio, ethylthio, methoxycarbonyl, ethoxycarbonyl, acetamido or carboxamido; R 2  represents hydrogen, fluorine, chlorine, bromine, iodine, lower alkoxyl, hydroxyl, lower alkyl; R 3  represents hydrogen, chlorine or lower alkyl; or R 1  and R 2  when on adjacent carbon atoms may together represent a polymethylene group containing from 3 to 5 carbon atoms; and n is 2, 3 or 4; and a pharmaceutically acceptable carrier, compounds of formula (I) except those wherein R 1  is a 2-methoxyl group, and 2,4-dimethyl-1-[2-(4-bromophenylsulphonamido)ethyl]pyrrolidine and 2,4-dimethyl-1-[2-(4-bromophenylsulphonamido)ethyl]pyrrolidine, a process for the preparation of compounds of the formula (I) and 2,4-dimethyl-1-[2-(4-bromophenylsulphonamido)ethyl]pyrrolidine and 2,4-dimethyl-1[2-(4-iodophenylsulphonamido)ethyl]pyrrolidine as antiarrhythymic agents.

CROSS-REFERENCE

This is a continuation of Ser. No. 148,140 filed May 9, 1980 and nowabandoned.

Various sulphonamides are known as chemical curiosities [see for exampleBraun et al, Annalen, 445, 253 (1925) or Curwain et al, J. Med. Chem.,14, 737 (1971)] or as pharmaceutically active agents [see for exampleWest German Patent Application No. 2623447, which relates to localanaesthetics, West German Patent Application No. 2710047 which relatesto anti-anginal compounds, and West German Patent Application No.2545496 which relates to platelet aggregation inhibitors].

However, none of these known sulphonamides have been reported asanti-arrhythmic agents. It is desirable to provide anti-arrhythmicagents possessing low acute toxicity. A group of such compounds has nowbeen found.

The present invention provides a pharmaceutical composition whichcomprises a compound of the formula (I): ##STR2## or a salt thereofwherein NR₂ represents a piperidyl, pyrrolidyl, morpholino or N-methylpiperazyl group, any of which may substituted by one or two methylgroups; R¹ represents fluorine, chlorine, bromine, iodine, loweralkoxyl, hydroxyl, acetoxyl, nitro, cyano, amino, dimethylamino, loweralkyl, trifluoromethyl, methylthio, ethylthio, methoxycarbonyl,ethoxycarbonyl, acetamido or carboxamido; R² represents hydrogen,fluorine, chlorine, bromine, iodine, lower alkoxyl, hydroxyl, loweralkyl; R³ represents hydrogen, chlorine or lower alkyl; or R¹ and R²when on adjacent carbon atoms may together represent a polymethylenegroup containing from 3 to 5 carbon atoms; and n is 2, 3 or 4; and apharmaceutically acceptable carrier.

When used herein lower alkyl means 1 to 4 carbon atoms and more suitablymeans 1 to 3 carbon atoms, preferably one carbon atom.

Apt values for NR₂ include piperidyl, 2-methylpiperidyl2,6-dimethylpiperidyl, pyrrolidyl, 2-methylpyrrolidyl,3-methylpyrrolidyl, 2,3-dimethylpyrrolidyl, 2,4-dimethylpyrrolidyl,2,5-dimethylpyrrolidyl, morpholino and N-methylpiperazyl.

Favoured values for NR₂ include the 2,6-dimethylpiperidyl, pyrrolidyl,2,4- and 2,5-dimethylpyrrolidyl N-methylpiperazyl and morpholino groups,more favourably the 2,4- and 2,5-dimethylpyrrolidyl groups. Preferablythe dimethylpyrrolidyl groups are in the form of their cis isomers. Ahighly favoured value for NR₂ is the cis-2,5-dimethylpyrrolidyl group.

From the foregoing it will be realised that certain suitable compoundsin the compositions of this invention include those of the formulae (II)to (VII). ##STR3## and salts thereof, wherein n, R¹, R² and R³ are asdefined in relation to formula (I).

n may be 2, 3 or 4 in formula (I).

More suitably n is 2 or 3 in respect of formula (I), but more suitably nis 2.

Certain favoured groups R¹ in respect of formula (I), include acetamido,amino, methyl, ethyl, isopropyl, methoxy, fluorine, chlorine, bromine,iodine, and trifluoromethyl. Preferred R¹ values include acetamido,amino and trifluoromethyl, in particular trifluoromethyl.

Certain favoured groups R² in respect of formula (I), include hydrogen,chlorine, methyl and iso-propyl. Preferred R² values include hydrogen.

Certain favoured groups R³ in respect of formula (I), include hydrogen,chlorine and methyl and iso-propyl. Preferred R³ values includehydrogen. Preferably R² and R³ are the same.

With respect to formula (II) R¹ is favourably amino, methyl, fluorine,iodine or trifluoromethyl. Favourably R² and R³ are the same and areeach hydrogen or methyl.

Suitably n is 2 or 3, preferably 2.

Certain favoured compounds of the formula (II) thus include those of theformula (X): ##STR4## and salts thereof, wherein L is 4-aminophenyl,4-fluorophenyl, 4-iodophenyl or 3-trifluoromethylphenyl.

Other favoured compounds include:

1-[3-(4-iodobenzenesulphonamido)propyl]pyrrolidine and

1-[3-(2,4,6-trimethylbenzenesulphonamido)propyl]pyrrolidine, and saltsthereof.

With respect to formula (III) R¹ is favourably chlorine ortrifluoromethyl preferably trifluoromethyl. Favourably R² and R³ are thesame and are each hydrogen or chlorine, preferably hydrogen.

When R¹ is chlorine, n is preferably 3, and when R¹ is trifluoromethyl,n is preferably 2.

Certain favoured compounds of the formula (III) thus include2,4-dimethyl-1-[3-(2,4,5-trichlorobenzenesulphonamido)propyl]pyrrolidineand salts thereof.

Certain preferred compounds include2,4-dimethyl-1-[2-(3'-trifluoromethylbenzenesulphonamido)ethyl]pyrrolidine,and salts thereof.

With respect to formula (IV), R¹ is preferably trifluoromethyl. R² andR³ are preferably the same and are each hydrogen.

n is preferably 2.

Certain preferred compounds of the formula (IV) thus include2,5-dimethyl-1-[2-(3-trifluoromethylbenzenesulphonamido)ethyl]pyrrolidineand salts thereof.

With respect to formula (V), R¹ is favourably trifluoromethyl. R² and R³are favourably the same and are each hydrogen.

n is preferably 2.

Certain favoured compounds of the formula (VI) thus includeN-[2-(4-acetamidobenzenesulphonamido)ethyl]morpholine and salts thereof.

With respect to formula (VII) R¹ is favourably chlorine, Favourably R²and R³ are the same and are each chlorine.

n is suitably 3.

Certain favoured compounds of the formula (VII) thus include1-[2-(2,3,4-trichlorobenzenesulphonamido)-propyl]piperazine and saltsthereof.

Compounds of the formulae (III) and (IV) and salts thereof arepreferred, in particular their cis isomers.

Certain particularly preferred compounds of the formula (I) thus includethose of the formulae (XI) and (XII): ##STR5## and salt thereof, whereinR¹ ₂ N is cis-2,4-dimethylpyrrolidyl and R² ₂ N iscis-2,5-dimethylpyrrolidyl.

It will of course be realised that when NR₂ in the compounds of theformula (I) is asymmetrically substituted by one methyl group, the NR₂group has a chiral centre. Compounds of the formula (I) containing suchNR₂ groups are the thus capable of existing in a number ofstereoisomeric forms.

The invention extends to compositions containing any of thestereoisomeric forms including enantiomers of the compounds of theformula (I) and to mixtures thereof, including racemates. The differentstereoisomeric forms may be separated one from the other by the usualmethods, or any given isomer may be obtained by stereospecific orasymmetric synthesis.

The salts of the compounds of the formulae (I) to (XII) include acidaddition salts and are preferably acid addition salts withpharmaceutically acceptable acids. Such acids may be inorganic ororganic acids such as hydrochloric, hydrobromic, sulphuric,methanesulphonic, acetic, citric, lactic, tartaric, propionic, benzoic,fumaric and the like.

The salts of the compounds of the formulae (I), to (XII) also includepharmaceutically acceptable quaternary ammonium salts. Examples of suchsalts include such compounds quaternised by compounds such as R⁴ --Ywherein R⁴ is C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and Y isan anion of an acid. Suitable examples of R⁴ include methyl, ethyl andn- and iso-propyl; and benzyl and phenylethyl. Suitable examples of Yinclude the halides such as chloride, bromide and iodide.

Examples of salts also include pharmaceutically acceptable internalsalts such as N-oxides.

The composition of this invention may be adapted for administration bymouth or by injection. Most suitably the composition will be inunit-dose form and such unit-doses will normally contain from 1 mg to100 mg and more usually from 2 mg to 50 mg of the active agent.

These compositions may be administered 1 to 6 times daily or more usual2 to 4 times daily in such manner that the daily dose for a 70 kg adultis about 1 mg to 250 mgs and more usually 50 mg to 200 mg, for example10 mg to 75 mg. The compositions of this invention may be fabricated inconventional manner, for example they may be presented as tablets orcapsules for oral administration or as dry powders sealed into ampoulesfor reconstitution with water or saline for injection. Tablets andcapsules may contain carriers such as disintegrants, binders,lubricants, colorants and the like in conventional manner. They maytherefore contain such agents as microcrystalline cellulose, lactose,starch, polyvinylpyrrolidone, sodium starch glycollate, magnesiumstearate and the like. Tablets may be prepared by conventional mixingand compressing operations and capsules may be prepared by conventionalmixing and filling operations.

Certain compounds of this invention are novel. This invention thereforealso provides compounds of formula (I) as hereinbefore defined exceptthose wherein R¹ is a 2-methoxyl group, and2,4-dimethyl-1-[2-(4-bromophenylsulphonamido)ethyl]pyrrolidine and2,4-dimethyl-1-[2-(4-iodophenylsulphonamido)ethyl]pyrrolidine.

Favoured and preferred compounds of this group include those sodescribed under formulae (I) to (XII).

A group of compounds within the novel compounds of the formula (I) arethose wherein R² and R³ are not both hydrogen.

Favoured compounds of this group include1-[3-(2,4,6-trimethylbenzenesulphonamido)propyl]pyrrolidine;

2,4-dimethyl-1-[3-(2,4,5-trichlorobenzenesulphonamido)propyl]pyrrolidine;and

4-methyl-1-[3-(2,3,4-trichlorobenzenesulphonamido)propyl]piperazine.

The invention in its relevant aspect extends to each of thestereoisomeric forms, including enantiomers, of the compounds of theformula (I) described above and to mixtures thereof, includingracemates.

The medicinal use of2,4-dimethyl-1-[2-(4-bromophenylsulphonamido)ethyl]pyrrolidine and2,4-dimethyl-1[2-(4-iodophenylsulphonamido)ethyl]pyrrolidine is novel.Accordingly the present invention also provides these two compounds asantiarrhythmic agents.

The invention also provides a method of treatment or prophylaxis ofcardiac arrhythmia in humans, comprising administering to the sufferer atherapeutically effective amount of a compound of the formula (I)

The compounds of this invention and salts thereof may be prepared by thereaction of a compound of the formula (XIV):

    R.sub.2 N--(CH.sub.2).sub.n --NH.sub.2                     (XIII)

wherein R₂ and n are as defined in relation to formula (I) and acompound of the formula (XIV): ##STR6## or a chemical equivalentthereof, wherein R¹, R² and R³ are as defined in relation to formula(I); and optionally forming a salt of the resultant compound of theformula (I).

Chemical equivalents of the compounds of the formula (VII) include thecorresponding bromide and iodide.

The preceding condensation reaction is generally effected at ambienttemperature and normal pressure in a convenient solvent such as benzeneor toluene optionally in the presence of a base. Removal of the solvent,for example by evaporation, yields the initial crude product, which willgenerally be the desired compound as free or its salt depending onwhether the reaction is carried out in the presence or absence of abase. The free basic product may be purified by crystallisation orchromatography; or a salt may be purified by crystallisation. If desireda salt may be converted into the free base by neutralisation and ifdesired the free base may be salified in conventional manner.

It will be realised that, in a compound of the formula (I),interconversion of suitable substituents R₁, R₂ or R₃ may be carried outby conventional methods after formation of a compound of the formula(I). By way of example an acetamido group may be converted to an aminogroup an alkoxyl or acetoxyl group may be converted to a hydroxyl group,a nitro group may be reduced to an amino group, by conventional methods.Accordingly it will be realised that compounds of the formula (I)containing the substituent R₁, R₂ or R₃ which is convertible to anotherR₁, R₂ or R₃ group respectively are useful intermediates and as suchform as important aspect of the invention.

It will also be realised that salts of the compounds of the formula (I)which are not pharmaceutically acceptable may be useful as intermediatesin the preparation of pharmaceutically acceptable salts of compounds ofthe formula (I) or the compounds of the formula (I) themselves, and assuch form an aspect of the present invention.

When NR₂ in the compounds of the formula (I) is substituted by twomethyl groups, these may be mutually cis or trans about the NR₂ ring. Amixture of cis and trans isomers of the compound of the formula (I) maybe synthesised non stereospecifically and the desired isomer separatedconventionally therefrom, e.g. by chromatography; or alternatively thecis or trans isomer may if desired be synthesised from the correspondingcis or trans form of the compound of the formula (VI).

Cis- and trans- forms of the compound of the formula (VI) are eitherknown as separate forms or may be separated conventionally e.g. bychromatography.

Racemates of compounds of the formula (I) wherein NR₂ is substituted byone or two methyl groups may be resolved conventionally, e.g. bysalification with a chiral acid and separation of the resultant salts.

The following Examples illustrate the invention.

EXAMPLE I 1-[2-(4-Acetylaminobenzenesulphonamido)ethyl]-pyrrolidiniumchloride (1)

4-Acetylaminobenzenesulphonylchloride (21.9 g) was added in portions toa solution of 1-(2-aminoethyl)pyrrolidine (10.7 g, 0.9 mol) in water(250 ml). The mixture was stirred for 9 hours at room temperature. Atthe end of the reaction, the solution has pH 6-7. A portion of themixture (165 ml) was removed and adjusted to pH 9.5. The precipitatefrom the mixture (4.9 g) was removed under suction and dissolved inethyl acetate (170 ml). The solution was filtered and HCl gas was passedthrough. Precipitated chloride was isolated and recrystallised fromabsolute ethanol (350 ml) to give the product (27.2 g).

M.P. 220° C. yield=78% of theoretical

C₁₄ H₂₁ N₃ O₃ S HCl, Mol. weight: 347,85

Compounds No: (2) and (5) were prepared in the same manner (see Table 1)

EXAMPLE II 1-[2-(4-Aminobenzenesulphonamido)ethyl]-pyrrolidiniumchloride (3)

(A) Conc. hydrochloric acid (20 ml) was added to 160 ml of the mixtureobtained in Example 1. This solution was warmed on a boiling water bathfor 5 hours. Thereafter the solution was neutralised with NaHCO₃,filtered and adjusted to pH 10. The sulphonamide separated as an oil andwas extracted with diethylether (4×100 ml) from the alkaline medium. Thecombined extracts were dried over Na₂ SO₄ and the solvent was removed bydistillation.

(B) The residue was dissolved in ethyl acetate and then HCl gas waspassed through. Precipitated chloride was removed by suction andrecrystallised from isopropanol to give the product (10.3 g).

M.P. 216° C. Yield=75% of theoretical

C₁₂ H₁₉ N₃ O₂ S HCl, Mol. weight: 305,84

Compound (4) was prepared analogously to step (A) above andrecrystallised from water.

Compound (6) was prepared analogously to steps (A) and (B) substitutingfumaric acid (essentially 1 aq.) for HCl gas.

EXAMPLE III N-[2-(4-Acetylaminobenzenesulphonamido)ethyl]-morpholine (7)

A saturated solution of NaHCO₃ (50 ml) was added toN-(2-aminoethyl)morpholine (7.5 g, 0.05 mol) dissolved in chloroform (50ml). Thereafter, 4-acetylaminobenzenesulphonylchloride (12.3 g, 0.05mol) was added in portions with vigorous stirring. The mixture wasstirred for 3 days at room temperature (pH 8.5). The chloroform layerwas separated with a separating funnel and the aqueous layer wasextracted with chloroform (3×100 ml). The combined chloroform extractswere dried over Na₂ SO₄, and the chloroform was removed by evaporation.

The residue was recrystallised from the following:

1. ethyl acetate

2. ethyl acetate/diethylether (1:1)

M.P. 114,5°-115,5° C. Yield 29% of theoretical

C₁₄ H₂₁ N₃ O₄ S Mol. weight: 327,46

Compound No. (8) (see Table 1) was prepared analogously.

EXAMPLE IV 1-[3-(4-Methoxybenzenesulphonamido)propyl]-pyrrolidiniumchloride (11)

4-Methoxybenzenesulphonylchloride (8.26 g, 0.04 mol) was added inportions with stirring to a solution of 1-(3-aminopropyl)-pyrrolidine(5.13 g, 0.04 mol) in 10% NaOH (100 ml), and the resulting mixture wasstirred at room temperature for the next 24 hours. Unreactedsulphonylchloride was filtered off, and the filtrate was adjusted to pH9,8 with dilute HCl.

Oily sulphonamide, which sparated out, was extracted with diethyl ether(4×100 ml) from the alcoholic mixture. The solvent was distilled off andthe residue was dissolved in ethyl acetate (200 ml). HCl gas was passedthrough this solution. The resulting chloride was removed by suction,washed with ethyl acetate and recrystallized from isopropanol to givethe product (6.0 g).

M.P. 159° C. Yield=45% of theoretical

C₁₄ H₂₂ N₂ O₃ S . HCl

Compounds No. (9), (10), (13), (14), (16) to (19) and (23) and

1-[2-(4-fluorobenzenesulphonamido)ethyl]pyrrolidinium chloride (15),

1-[2-(4-iodobenzenesulphonamido)ethyl]pyrrolidinium chloride (21),

1-[3-(4-iodobenzenesulphonamido)propyl]pyrrolidinium chloride (22),

1-[2-(3-trifluoromethylbenzenesulphonamido)ethyl]pyrrolidinium chloride,

cis- (27) and trans- (28)2,5-dimethyl-1-[2-(3-trifluoromethylbenzenesulphonamido)ethyl]pyrolidiniumchloride, and

2,4-dimethyl-1-[2-(3-trifluoromethylbenzenesulphonamido)ethyl]pyrrolidiniumchloride (29) (cis-, trans- mixture)

were prepared analogously.

EXAMPLE V2,4-Dimethyl-1-[3-(4-iodobenzenesulphonamido)propyl]pyrrolidine (20)

A solution of 2,4-dimethyl-1-(3-aminopropyl)pyrrolidine (4.7 g, 0.03mol) in benzene (20 ml) was added dropwise to a solution of4-iodobenzenesulphonylchloride (9.1 g, 0.03 mol) benzene (80 ml). Afterstirring the resulting mixture for six hours at room temperature, thereaction product separated as an oil. The reaction mixture wasevaporated, and the residue was dissolved in absolute alcohol (800 ml)and boiled with charcoal.

The charcoal was filtered off, and the solution was diluted with wateruntil precipitation occurred. The reaction product was evacuated,dissolved in dilute HCl and once more boiled with charcoal and filtered.The solution was made alkaline and the resulting precipitate of (20) wasremoved by suction.

M.P. 123° C., Yield=27% of theoretical

Mol. weight 422,32

Compounds No. (12), (24) and (30) were prepared in the same manner.

EXAMPLE VI 1-[3-(4-Carbethoxy-benzenesulphonamido)-propyl]pyrrolidiniumchloride (25) (see Table 1)

1-[3-(4-Cyanobenzenesulphonamido)propyl]pyrrolidinium chloride (9 g) wasboiled with 25% caustic soda solution (50 ml) for three hours. Duringcooling the resulting solid mass was acidified with conc. HCl (30 ml)and warmed briefly. Repeated cooling yielded a white precipitate, whichwas removed by suction and dried in vacuo, to yield1-[3-(4-carboxylbenzenesulphonamido)propyl]pyrrolidinium chloride.

Dry 1-[3-(4-carboxy-benzenesulphonamide)-propyl]pyrrolidinium chloride(9 g), absolute alcohol (25 ml) and conc. H₂ SO₄ (0.3 ml) were boiledunder reflux for 9 hours. Thereafter, the solvent was evaporated, andthe residue was dissolved in water. The aqueous solution was adjusted topH 10 with caustic soda solution and the resulting emulsion wasextracted with chloroform (3×50 ml). The combined chloroform extractswere washed with water (50 ml), dried over Na₂ SO₄ and evaporated todryness. The residue (8,6 g) was dissolved in ethyl acetate (150 ml),and HCl gas was passed through the solution. The resulting precipitatepassed through the solution. The resulting precipitate was removed bysuction and recrystallised from isopropanol.

M.P. 187° C. Yield=67% of theoretical

C₁₆ H₂₄ N₂ O₄ S . HCl Mol. weight: 376,90

EXAMPLE VII2,4-Dimethyl-1-[3-(2,5-dichlorbenzenesulphonamido)propyl]-pyrrolidine(33) (see Table 2)

2,4-Dimethyl-1-(3-aminopropyl) pyrrolidine in (4.7 g, 0.03 mol) benzene(30 ml) was added dropwise at room temperature to a solution of2,5-dichlorobenzenesulphonylchloride (7.3 g, 0.03 ml) in benzene (100ml). Thereafter, the mixture was stirred for 4 days at room temperatureuntil the reaction was complete. Finally, the reaction product wasobtained as a viscous, oily paste. The benzene mother liquor wasdecanted. The residue was dissolved in water, the solution was adjustedto pH 9.8 with 10% NaOH and extractes with petroleum ether (40°-60°)(4×100 ml). The combined extracts were dried over Na₂ SO₄ andevaporated. The residue (5 g) was recrystallised twice from 100 mlpetroleum ether to yield the product (3.7 g as white needles), m.p.65°-67° C. Yield=67% of theoretical

EXAMPLE VIII2,4-Dimethyl-1-[3-(2,4,5-trichlorobenzene-sulphonamido)propyl]-pyrrolidiniumchloride (38)

Whilst stirring, a solution of2,4-dimethyl-1-(3-aminopropyl)-pyrrolidine (4.67 g, 0.03 mol)benzene (20ml) was added dropwise to a solution of2,4,5-trichlorobenzenesulphonylchloride (8.4 g, 0.03 mol) benzene (80ml). The reaction mixture was stirred for a further eight hours at roomtemperature, whereby the reaction product (38) crystallised from themixture. The precipitate was removed by suction and washed with benzeneon the suction filter. The crude chloride was recrystallised fromisopropanol (100 ml) to obtain the product (8.7 g).

M.p. 114°-116° C., Mol. Wt. 436,22 C₁₅ H₂₁ N₂ O₂ SCl₃. HCl

Yield=67% of theoretical

Compounds No. (32), (35), (37), (39), (40), (43), (45), (46), (50) and(53) and

4-methyl-1-[3-(2,3,4-trichlorobenzenesulphonamido)propyl]-1,4-diazoniacyclohexanedichloride (36)3,5-dimethyl-1-[2-(2,4,6-trimethylbenzenesulphonamido)ethyl]piperidiniumchloride (54) were prepared analogously.

Compound (51) was prepared substantially analogously, but the chloridewas neutralised and the resultant free base treated with fumaric acid togive the fumarate (51).

EXAMPLE IX 2,4-Dimethyl-1-[3-(2,3,4-trichlorobenzenesulphonamido)propyl]-pyrrolidine (34) (see Table 2)

A solution of 2,4-dimethyl-1-(3-amino-propyl) pyrrolidine (9.3 g, 0.06mol) benzene (50 ml) was added dropwise, whilst stirring, to a solutionof 2,3,4-trichlorobenzenesulphonylchloride (17.6 g, 0.06 mol) benzene(200 ml). The mixture was stirred for a further 5 hours at roomtemperature, whereby the reaction mixture was evaporated to dryness andthe residue was dissolved in water (250 ml). The aqueous solution wasextracted with diethyl ether (2×50 ml) to remove unreactedsulphochloride. The aqueous solution was then adjusted with caustic sodasolution to pH 9,8 and the alcoholic solution was extracted with diethylether (2×100 ml). The combined extracts were dried over Na₂ SO₄, and thesolvent was distilled off. The residue was recrystallised fromisopropanol (100 ml). The product (34) (9 g) was obtained. The filtratewas diluted with the same quantity of water to obtain a further 6,2 g of(34).

M.p. 73°-75° C., Mol. Wt. 399.76 C₁₅ H₂₁ N₃ O₂ SCl₃

Yield=61% of theoretical

Compound (41) (see Table 2) was prepared analogously.

EXAMPLE X 2,4-Dimethyl-1-(2-β-tetrahydronaphthalene sulphonamido)ethyl-pyrrolidinium chloride (56) (see Table 3)

Whilst stirring, a solution of 2,4-dimethyl-1-(3-aminoethyl)-pyrrolidine(7.2 g, 0.05 mol) in benzene (20 ml) was added dropwise to a solution ofβ-tetrahydronaphthalene sulphochloride (11.5 g, 0.05 mol) in benzene (80ml). The reaction mixture was stirred for a further eight hours at roomtemperature, whereby the reaction product was recrystallized from themixture as hydrochloride. The precipitate was removed by suction andwashed with benzene on the suction filter. Crude hydrochloride wasrecrystallized from isopropanol (100 ml) to obtain the product (9.2 g).

M.p. 132°-134° C., Mol.Wt. 372.95 C₁₈ H₂₈ N₂ O₂ S . HCl

Yield=49.4% of theoretical

Compounds (42), (43), (45) to (47) (see Table 2) and (57) (see Table 3),and

2,6-dimethyl-1-[2-(3-trifluoromethylbenzenesulphonamido)ethyl]piperidiniumchloride (31) and

1-[3-(2,4,6-trimethylbenzenesulphonamido)propyl]pyrrolidinium chloride(44) (see Table 2)

were prepared analogously.

EXAMPLE XI Cis-(27) and trans-(28)2,5-dimethyl-1-[2-(3-trifluoromethylbenzenesulphonamido)ethyl]pyrrolidiniumchloride

2,5-dimethyl-1-(2-aminoethyl)-pyrrolidine (8.4 g, 0.05 mol) in toluene(20 ml) was added dropwise at room temperature to a solution of3-trifluoromethylbenzenesulphomylchloride in toluene (180 ml).Thereafter the mixture was stirred for 6 hours. Finally the mixture wasstirred with Na₂ CO₃ solution (6.15 g in 100 ml water). The toluenelayer was separated off and dried over Na₂ SO₄, and the solvent wasremoved by distillation. The residue (15 g) was purified and separatedinto its isomeric components on silica gel (14 g) by elution withchloroform/methanol/cone ammonia (190:9:1)

fraction I 4.4 l--3-trifluoromethylbenzenesulphomylchloride

fraction II 550 ml--product A

fraction III 500 ml--mixture

fraction IV 2500 ml--product B

Fraction II: the solvent was removed by distillation and the residue (11g) was dissolved in ethyl acetate (20 ml). HCl gas was passed throughthis solution. On cooling, the chloride crystallized out and was removedby suction. Yield 5.2 g (23% of theoretical) Mp 135° C.

Fraction IV: the solvent was removed by distillation and the residue(1.5 g) was dissolved in ethyl acetate, HCl gas was passed through thissolution. The precipitate was removed by suction and recrystalized fromisopropanol (30 ml). The chloride obtained (1.6 g, 10% of theoretical)had Mp 138° C.

Product A Mp 135° C. C₁₅ H₂₁ N₂ O₂ SF₃

NMR: 1.41 ppm (6H, d: J6,5 Hz, 2CH₃) cis-isomer (27)

Product B Mp 178° C. C₁₅ H₂₁ N₂ O₂ SF₃.HCl

NMR: 1.15 ppm 13H, d: J7 Hz, CH₃) trans-isomer (28) 1.34 ppm (3H, d:J6.5 Hz, CH₃) Cis- (55) and trans- (54)3,5-dimethyl-1-[2-(2,4,6-trimethylbenzenesulphonamido)ethyl]piperidiniumchloride were prepared and separated in an analogues manner.

    ______________________________________                                        Product A Mp 175° C. C.sub.19 H.sub.26 N.sub.2 o.sub.2 S.HCl           NMR:    9.85 ppm (3H, d: J 5.5 Hz, CH.sub.3)                                                              trans-isomer (54)                                         1.18 ppm (3H, d: J 7.5 Hz, CH.sub.3)                                  Product B Mp 235° C. C.sub.19 H.sub.26 N.sub.2 O.sub.2 S.HCl           NMR:    9.89 ppm (6H, d: J 5.5 Hz, 2CH.sub.3)                                                             cis-isomer (55)                                   ______________________________________                                    

EXAMPLE XII1-[3-(2,4,6-trimethylbenzenesulphonamido)-propyl]-2-methylpiperidiniumchloride (48)

1-(3-aminopropyl)-2-methyl-piperidine (8.02 g, 0.05 mol) in benzene (50ml) was added dropwise at room temperature to a solution of2,4,6-trimethylbenzenesulphochloride (11.05 g, 0.05 mol) in benzene (150ml). Thereafter, the mixture was stirred for 8 hours, whereby thechloride reaction product precipitated from the mixture. The precipitatewas removed by suction and washed with benzene on the suction filter.The crude chloride (18.2 g) was dissolved in water (100 ml). The aqueoussolution was then adjusted with caustic soda solution to pH 9 andextracted with chloroform (2×100 ml). The combined extracts were driedover Na₂ SO₄, and solvent was removed by distillation. The residue wasdissolved in ethyl acetate (150 ml) and HCl gas was passed through thissolution. The ethyl acetate was temoved by distillation and the residuewas dissolved in hot isopropanol. After cooling to -6° C. crystallizedchloride and was removed by suction.

Yield 9.7 g (5.1% of theoretical) Mp 153° C. C₁₈ H₃₀ N₂ O₂ S.HCl

Compounds (49), 52 and 53 were prepared in the same manner (see Table2).

DESCRIPTION 1 Pharmacology of Compounds

Test Procedure to Demonstrate Antiarrythmic Effects ElectrostimulationTest

According to the method of SZEKERES, L. and PAPP, G. J.,(Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 245, 70 (1963),arrhythmias are induced in Guinea pigs by electostimulation of the rightventricle of the heart. The animals are anesthetized with Urethane (1.2g/kg i.p.) and artifically respired before a needle electrode isinserted in the right ventricle of the heart. Substances are givenintraduodenally 30 min before the stimulation. The voltage needed forinduction of extrasystoles in control animals (n=6) is compared withthat required for induction of arrhythmias in treated animals (n=6). Thedifference is statistically evaluated by the unpaired t-test (STUDENT).

This method was used to evaluate the compounds present invention. Theresults are shown in following Tables 1 to 3.

                                      TABLE 1                                     __________________________________________________________________________     ##STR7##                                                                                                            % increase                                                                    of voltage                                                                    electro                                                                       stimulation                                                               Yield                                                                             test dose                                                                 % of                                                                              32 mg/kg i.d.                          No.                                                                              A         n R.sub.1                                                                          R.sub.2                                                                              Salt Mp °C.                                                                      theory                                                                            (GP; n = 6)                            __________________________________________________________________________        ##STR8## 2 N  NHCOCH.sub.3                                                                         HCl  220 EtOH                                                                           22  21.4*                                  2                                                                                 ##STR9## 3 H  NHCOCH.sub.3                                                                         HCl  183 EtOH                                                                           28  14.3                                   3                                                                                 ##STR10##                                                                              2 H  NH.sub.2                                                                             HCl  216 IPA                                                                            23  36.2*                                  4                                                                                 ##STR11##                                                                              3 H  NH.sub.2                                                                             --   127 H.sub.2 O                                                                      28  24.1*                                  5                                                                                 ##STR12##                                                                              2 H  NHCOCH.sub.3                                                                         HCl  188.5                                                                              24.3                                                                              7.0                                    6                                                                                 ##STR13##                                                                              2 H  NH.sub.2                                                                             C.sub.4 H.sub.4 O.sub.4                                                            157- 158                                                                           45.6                                                                              15.7                                   7                                                                                 ##STR14##                                                                              2 H  NHCOCH.sub.3                                                                         --   114.5- 115                                                                         29.1                                                                              43.3*                                  8                                                                                 ##STR15##                                                                              3 H  NHCOCH.sub.3                                                                         --   97   63  14.3*                                  9                                                                                 ##STR16##                                                                              3 H  CH.sub.3                                                                             HCl  171 IPA                                                                            20  22.5*                                  10                                                                                ##STR17##                                                                              2 H  OCH.sub.3                                                                            HCl  118 IPA                                                                            24  10.0*                                  11                                                                                ##STR18##                                                                              3 H  OCH.sub.3                                                                            HCl  159 IPA                                                                            45  22.5*                                  12                                                                                ##STR19##                                                                              3 H  OCH.sub.3                                                                            HCl  197 IPA                                                                            56  2.3                                    13                                                                                ##STR20##                                                                              2 H  OCH.sub.3                                                                            HCl  186 IPA                                                                            34  4.6                                    14                                                                                ##STR21##                                                                              3 H  OCH.sub.3                                                                            HCl  172 IPA                                                                            61  11.7                                   15                                                                                ##STR22##                                                                              2 H  F      HCl  125 IPA                                                                            37  24.8*                                  16                                                                                ##STR23##                                                                              2 H  Cl     HCl  136 EtOH                                                                           48.5                                                                              9.1                                    17                                                                                ##STR24##                                                                              2 H  Cl     HCl  161 IPA                                                                            34  21.5*                                  18                                                                                ##STR25##                                                                              3 H  Cl     HCl  210 IPA                                                                            34  19.6                                   19                                                                                ##STR26##                                                                              2 H  Br     HCl  140- 142 IPA                                                                       57  19.8*                                  20                                                                                ##STR27##                                                                              3 H  I      --   123 H.sub.2 O                                                                      26  11.8*                                  21                                                                                ##STR28##                                                                              2 H  I      HCl  175 IPA                                                                            30  30.9*                                  22                                                                                ##STR29##                                                                              3 H  I      HCl  212 IPA                                                                            45  30.9*                                  23                                                                                ##STR30##                                                                              3 H  I      HCl  204 IPA                                                                            38  19.7                                   24                                                                                ##STR31##                                                                              3 H  SCH.sub.3                                                                            HCl  166 IPA                                                                            79  12.9*                                  25                                                                                ##STR32##                                                                              3 H                                                                                 ##STR33##                                                                           HCl  183 IPA                                                                            67  16.92*                                 26                                                                                ##STR34##                                                                              2 CF.sub.3                                                                         H      HCl  153 IPA                                                                            46  38.0*                                  27                                                                                ##STR35##                                                                              2 CF.sub.3                                                                         H      HCl  135 IPA                                                                            23  60.2*                                  28                                                                                ##STR36##                                                                              2 CF.sub.3                                                                         H      HCl  178  10  37.3*                                  29                                                                                ##STR37##                                                                              2 CF.sub.3                                                                         H      HCl  124 EtOH                                                                           46  50.0*                                  30                                                                                ##STR38##                                                                              2 CF.sub.3                                                                         H      HCl  219  47.3                                                                              1.3                                    31                                                                                ##STR39##                                                                              2 CF.sub.3                                                                         H      HCl  129 EE/PE                                                                          51  31.8*                                  __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR40##                                                                                                              % increase                                                                    of voltage                                                                    electro                                                                       stimulation                                                               Yield                                                                             test dose                           No.                                                                              A          n R.sub.1                                                                          R.sub.2                                                                         R.sub.3                                                                          R.sub.4                                                                         R.sub.5                                                                          Salt Mp °C.                                                                     %   32 mg/kg i.d.                       __________________________________________________________________________    32                                                                                ##STR41## 3 Cl H H  Cl                                                                              H  HCl  203 IPA                                                                           33.9                                                                              7.5*                                33                                                                                ##STR42## 3 Cl H H  Cl                                                                              H  --   65- 67 PA                                                                         67  3.7                                 34                                                                                ##STR43## 3 Cl Cl                                                                              Cl H H  --   73- 75 IPA                                                                        61  18.75*                              35                                                                                ##STR44## 3 Cl Cl                                                                              Cl H H  HCl  98 IPA                                                                            65.5                                                                              1.6                                 36                                                                                ##STR45## 3 Cl Cl                                                                              Cl H H  2HCl >280                                                                              71  25.8*                               37                                                                                ##STR46## 2 Cl H Cl Cl                                                                              H  HCl  191 68  14.8*                               38                                                                                ##STR47## 3 Cl H Cl Cl                                                                              H  HCl  114 IPA                                                                           66.5                                                                              28.9*                               39                                                                                ##STR48## 2 Cl H Cl Cl                                                                              H  HCl  128.5- 130 EtOH                                                                   52.6                                                                              11.3*                               40                                                                                ##STR49## 3 Cl H Cl Cl                                                                              H  HCl  195- 197 EtOH                                                                     50  13.9                                41                                                                                ##STR50## 3 Cl H Cl Cl                                                                              H  --   145 IPA                                                                           55  10.6                                42                                                                                ##STR51## 3 Cl H Cl Cl                                                                              H  HCl  161 IPA                                                                           63  20.0*                               43                                                                                ##STR52## 3 Cl H Cl Cl                                                                              H  HCl  291 EtOH                                                                          42  4.1                                 44                                                                                ##STR53## 3 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  201 IPA                                                                           74.5                                                                              24.8*                               45                                                                                ##STR54## 2 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  153- 154 IPA                                                                      62.9                                                                              2.3                                 46                                                                                ##STR55## 3 i-pr                                                                             H i-pr                                                                             H i-pr                                                                             HCl  217- 219 IPA                                                                      70.1                                    47                                                                                ##STR56## 3 i-pr                                                                             H i-pr                                                                             H i-pr                                                                             HCl  224- 225 H.sub.2 O                                                                43.5                                                                              17.9*                               48                                                                                ##STR57## 3 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  153 IPA                                                                           57.1                                                                              6.0*                                49                                                                                ##STR58## 3 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         2HCl 264 IPA                                                                           42.7                                                                              7.5*                                50                                                                                ##STR59## 2 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  176- 177 EtOH                                                                     64.6                                                                              10.6*                               51                                                                                ##STR60## 2 i-pr                                                                             H i-pr                                                                             H i-pr                                                                             C.sub.4 H.sub.4 O.sub.4                                                            244- 245 EtOH                                                                     42.16                                                                             1.5                                 52                                                                                ##STR61## 3 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  191- 192 EtOH                                                                     52.5                                                                              1.15                                53                                                                                ##STR62## 2 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  193 IPA                                                                           59  16.7*                                  trans-                                                                     54                                                                                ##STR63## 2 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  175 IPA                                                                           20                                         cis-                                                                       55                                                                                ##STR64## 2 CH.sub.3                                                                         H CH.sub.3                                                                         H CH.sub.3                                                                         HCl  236 EtOH                                                                          46                                      __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR65##                                                                                                           % increase                                                                    of voltage                                                                    electro                                                                       stimulation                                                               Yield                                                                             test dose                              No.                                                                              A         n R.sub.1                                                                            R.sub.2                                                                          R.sub.3                                                                         R.sub.4                                                                         Salt                                                                             Mp °C.                                                                      %   32 mg/kg i.d.                          __________________________________________________________________________    56                                                                                ##STR66##                                                                              2                                                                                ##STR67##                                                                            H H HCl                                                                              132-134 IPA                                                                        49.4                                                                              7.46                                   57                                                                                ##STR68##                                                                              2                                                                                ##STR69##                                                                            H H HCl                                                                              208- 210                                                                           56.5                                                                              7.8                                    __________________________________________________________________________

Toxicity

No toxic effects were observed at the test dosages.

I claim:
 1. A compound selected from the group consisting of sulfonamideof the formula: ##STR70## and the pharmaceutically acceptable saltsthereof wherein A is a cyclic amino radical selected from the groupconsisting of pyrrolidino, 2,4-dimethylpyrrolidino,2,5-dimethylpyrrolidino, 2,4-dimethylpiperidino and 4-methylpiperazine;andn has a value of 2 or
 3. 2. A compound according to claim 1 wherein nis 2 and A is pyrrolidino, 2,4-dimethylpyrrolidino or2,5-dimethypyrrolidino.
 3. A compound according to claim 1 wherein saidsulfonamide is2,4-dimethyl-1-[2-(3-trifluoromethylbenzenesulfonamido)ethyl]pyrrolidine.4. A compound according to claim 3 wherein the conformation of themethyl groups is cis.
 5. A compound according to claim 1 wherein saidsulfonamide is2,5-dimethyl-1-[2-(3-trifluoromethylbenzenesulfonamido)ethyl]pyrrolidine.6. A compound according to claim 5 wherein the conformation of themethyl groups is cis.
 7. The method of effecting an anti-arrhythmicresponse in humans and other animals which comprises administeringthereto an effective amount of a compound according to claim
 1. 8. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 sufficient to effect an anti-arrhythmic response incombination with a pharmaceutical carrier.